2-Methyl-2-triazolylmethylpenam-3-carboxylic acid S,S-dioxide, is a β-lactam compound represented by the following formula (1) and generally called “tazobactam”:

As tazobactam per se exhibits very weak antibacterial activity, it is not used alone as an antibacterial agent. However, it irreversively binds to various β-lactamases produced by microorganisms and exhibits ability to inhibit β-lactamase activities. Therefore, tazobactam is used in combination with various existing antibacterial agents that are inactivated by β-lactamases, allowing such antibacterial agents to exhibit their inherent antibacterial activity against β-lactamase-producing microorganisms (Katsuji SAKAI, Recent Antibiotics Manual 10th ed., page 113). For example, pharmaceuticals containing a sodium salt of tazobactam and piperacillin (a type of antibacterial agent inactivated by β-lactamase) as active ingredients are commercially available and widely used.
Heretofore, tazobactam has been produced, according to the method disclosed in Japanese Patent No. 2648750, by reacting cresol and a β-lactam compound represented by formula (2):
wherein R represents benzyl having electron-donating substituent(s) on the phenyl ring, diphenylmethyl that may have electron-donating substituent(s) on the phenyl ring(s), or tert-butyl.
Although tazobactam is barely water-soluble, when it is converted into a salt, it becomes water-soluble. Tazobactam is isolated and purified by taking advantage of this property.
In particular, in the aforementioned patent, a reaction mixture containing tazobactam formed is mixed with a basic compound, water and a hydrophobic organic solvent, thereby converting the tazobactam into a salt. Subsequently, the tazobactam salt is extracted into the aqueous layer, and this aqueous layer is acidified to crystallize the desired tazobactam. The above-described patent does not specify the temperature at which the aqueous layer is acidified. In the examples therein, however, the aqueous layer is cooled to 0 to 5° C. and then adjusted to an acidic range.
The tazobactam crystals obtained according to the method disclosed in the aforementioned patent exhibit poor stability and pose a problem of impaired purity due to decomposition after long-term storage at room temperature.
When tazobactam purity decreased even to a small degree, it fails to meet pharmaceutical standards and cannot be formulated. Moreover, due to the decomposition of tazobactam, β-lactamase inhibiting activity is impaired and antibacterial agents used in combination therewith may not sufficiently exhibit their antibacterial activities. Therefore, in order to use a combination of tazobactam and antibacterial agents as a medicament, it is necessary to prevent the purity of tazobactam from being decreased.
To this end, techniques to avoid decrease in purity such as storage under refrigerated conditions are applied to the tazobactam produced according to the aforementioned method.